1. Field of the Invention
The present invention relates to the field of prophylaxis and treatment of hypotension. Most particularly, the present invention proposes methods for the control and inhibition of hypotension or systemic shock through the administration of particularly defined formulations with limited nitric oxide-generating potential. The present invention also relates to specially tailored nutritional formulations for patients at risk of hypotension or systemic shock which include low concentrations of arginine or are arginine-free. Particular embodiments of the formulations also include ornithine or citrulline as urea cycle substrates. Anti-hypotensive TPN formulations for the general nutritional support of patients are also provided as within the scope of the present invention.
2. Background of the Art
Hypotension, or low blood pressure, is a complicating and often life-threatening condition attendant to shock, traumatic injury, sepsis, the administration of immunomodulators, as well as other situations. Thus, the risk of hypotension affects a significant number of persons throughout the world. For example, septic shock, a life-threatening complication of bacterial infections, affects 150,000 to 300,000 patients annually in the United States alone..sup.1
The cardiovascular collapse and multiple metabolic derangements associated with septic shock are due largely to bacterial endotoxin (ET), which has been shown to elicit a septic shock-like condition when administered to animals.sup.2. ET is known to stimulate the synthesis and release of several cytokines and biological mediators having hypotensive activity; among the factors released, TNF, platelet activating factor (PAF), prostacyclin and complement-derived C5a anaphylatoxin have been proposed as contributors to the cardiovascular collapse of septic shock.sup.3-6.
Although it has been shown that animals pretreated with anti-TNF antibodies.sup.7, PAF receptor antagonists.sup.8, and prostacyclin synthesis inhibitors.sup.9 are significantly protected against septic shock, the relative importance of these mediators in the pathology of septic shock is presently uncertain.
There is also evidence that some of these mediators may act indirectly via release of secondary mediators. Thus, the finding that anti-TNF antibodies have little or no protective effect when given after ET exposure.sup.7 suggests that TNF stimulates the production of another factor that is the actual hypotensive agent. Once initiated, synthesis and release of that factor can apparently continue even in the absence of detectable TNF. In 1980, Furchgott et al. (1980).sup.10 demonstrated that endothelial cells, which line blood vessels, can be stimulated to release a substance which relaxes vascular smooth muscle (i.e., causes vasodilatation). Since the chemical nature of this substance was completely unknown, it was simply named endothelium-derived relaxing factor (EDRF). It is hypothesized that many naturally-occurring substances which act as physiological vasodilators mediate all or part of their action by stimulating release of EDRF; these substances include, acetylcholine, histamine, bradykinin, leukotrienes, ADP, ATP, substance P, serotonin, thrombin and others.
The extremely short lifetime of EDRF (several seconds) hampered early efforts to chemically identify this molecule. In 1987, several laboratories suggested that EDRF may be nitric oxide (NO), which spontaneously decomposes to nitrate and nitrite. However, the fundamental problem in accepting this NO hypothesis was that mammalian systems were not known to contain an enzymatic pathway which could synthesize NO; additionally, a likely precursor for NO biosynthesis was unknown.
After observing that the arginine analog L-N.sup.G -methylarginine (L-NNA) could inhibit vascular EDRF/NO synthesis induced by acetylcholine and histamine, and that EDRF/NO synthesis could be restored by adding excess L-arginine, certain of the present inventors proposed that arginine is the physiological precursor of EDRF/NO biosynthesis.sup.11. Certain of the present inventors later demonstrated that inhibition of EDRF/NO synthesis in the anesthetized guinea pig raises blood pressure.
The enzyme responsible for NO synthesis (nitric oxide synthase) has been partially characterized by some of the present inventors.sup.14 and acts to oxidize a terminal nitrogen of the quanidino group of arginine, resulting in production of nitric oxide and citrulline. Macrophage-derived nitric oxide is now considered an important tumoricidal and bactericidal agent.
It has been reported that macrophage cells become "activated" by 12-36 hour after treatment with gamma-interferon, bacterial endotoxin and various cytokines in vitro. However, this in vitro "activation" system had been associated only with the initiation of tumor cell killing.
However, none of the literature or studies available prior to the present inventors work associated hypotension with nitric oxide, or the involvement of macrophages with hypotension.
Macrophages are a quantitatively insignificant component of normal blood vessel walls, and have never been shown to play any role in blood pressure regulation; i.e., there existed no biochemical, physiological or immunological data to suggest that macrophages had any role in pathological hypotension. Thus, the inventors sought to investigate the role of nitric oxide in systems relevant to the manifestation of hypotension, specifically the role of cytokine induced pathological hypotension, particularly on cells which comprise blood vessel walls.
Cytokines are well known to cause morphological and functional alterations in endothelial cells described as "endothelial cell activation". Distinct immune-mediators such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and gamma-interferon (IFN) appear to induce different, but partially overlapping, patterns of endothelial cell activation including increased procoagulant activity.sup.16, PGI2 production.sup.17, HLA antigen expression.sup.18 and lymphocyte adhesion molecule activation. Although these cytokines are reported to cause hypotension, vascular hemorrhage, and ischemia, the underlying mechanisms of altered vasoactivity are unclear.sup.19,20.
In both clinical and animal studies on the effects of biological response modifiers.sup.21,22, a major dose limiting toxicity has been hypotension and vascular leakage. The inventors have observed that endotoxin and tumor necrosis factor can induce over production of nitric oxide in animals..sup.23,24 Nitric oxide is a vasoactive substance which controls resting blood pressure..sup.12 This led the present inventors to postulate that hypotension in humans resulting from administration of biological response modifiers or from the development of overwhelming bacterial infections is due to excessive production of nitric oxide in sufficient concentration to relax vasoconstriction. However, macrophages are known to compose quantitatively only an insignificant component of normal blood vessel walls. Moreover, as a practical matter, it was unlikely that the amount of nitric oxide generated by circulating macrophages would be sufficient to elicit a "hypotensive" effect physiologically, as nitric oxide is not produced in vast enough quantities by the limited number of macrophages in blood vessel walls to produce such a pronounced physiological response. This, together with the recognized short half-life nitric oxide in vivo (3-5 seconds), diminished the theory that macrophage-derived nitric oxide was involved in hypotension.
The inventors also observed that nitric oxide is derived from the amino acid L-arginine..sup.11,25 L-arginine is a typical ingredient in commercially available TPN (total parenteral nutrition) formulations.
The inventors postulated that: 1) other cell types were possibly linked to pathological hypotension, such as those cells associated with blood vessel walls (endothelial cells); 2) vascular (e.g., endothelial) cells may be stimulated to produce NO by stimuli similar to those stimuli found to trigger NO generation by macrophage; and 3) septic shock (i.e., systemic vasodilatation induced by bacterial endotoxin) may result from massive activation of No biosynthesis by cells which are a quantitatively significant component of normal blood vessel walls.
As hypotension has been observed in patients maintained on standard TPN formulations, a potential valuable improvement in managing the risk of hypotension in these TPN-receiving patients is postulated by the inventors to be provided through a modified TPN formulation which reduces or eliminates the potential synthesis of nitric oxide. As the present inventors have observed that nitric oxide is derived from the amino acid arginine, the modification of a TPN formulation to reduce or eliminate the availability of arginine will reduce the production of nitric oxide and the hypotensive effects nitric oxide causes in patients receiving or producing endotoxin, or receiving tumor necrosis factor, or any other of a variety of biological response modifiers.
A TPN regimen of low or essentially arginine-free formulations is proposed by the inventors to reduce, if not eliminate, the risk of hypotension and septic shock in patients with bacterial infections. Clinical regimens which typically require the administration of a TPN formulation include, for example, nutritional support of cancer patients and others who have no or limited ability to tolerate oral feeding.